SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α

Abstract

Background/Aims: The chondroitin sulfate proteoglycan serglycin (SRGN), a hematopoietic cell granule proteoglycan, has been implicated in promoting tumor metastasis; however, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the SRGN gene expression and its regulation as downstream signaling of hypoxia-inducible transcription factor 1 alpha (HIF-1α) in colorectal cancer (CRC) cells and tissues. Methods: The expression of SRGN was analyzed in CRC specimens for its correlation with progression and metastasis. Using chromatin-immunoprecipitation (ChIP), quantitative real-time PCR, Western blot, and transwell assay, the functional role and underlying mechanism of SRGN in CRC metastasis were elucidated. Thus, this study provides evidence of a critical role of SRGN in metastatic progression of CRC. Results: Our results indicated that SRGN overexpression was significantly associated with poor prognosis in CRC specimens. SRGN overexpression promoted CRC cell migration and invasion in vitro; however, SRGN depletion exhibited contrasting effects. Mechanistic investigations revealed that HIF-1α regulated SRGN transcription via physically binding to a hypoxia response element in its promoter region. Conclusions: In conclusion, we demonstrated that dysregulated HIF-1α/SRGN signaling promotes CRC progression and metastasis. SRGN may serve as a potential candidate therapeutic target for metastatic CRC.

Identification of Common Differentially Expressed Genes and Potential Therapeutic Targets in Ulcerative Colitis and Rheumatoid Arthritis

“…SRGN encodes the proteoglycan protein, and is mainly expressed in hematopoietic cells. Many studies have confirmed that SRGN promotes tumor invasion and metastasis in colorectal cancer, non-small cell lung cancers, multiple myeloma, nasopharyngeal carcinoma, and breast cancer (Li et al, 2011;Korpetinou et al, 2013;Purushothaman and Toole, 2014;Guo et al, 2017;Xu et al, 2018). SRGN is also involved in inflammatory processes through the regulation of numerous inflammatory mediators such as TNF-α, and activating the NF-κB signaling pathway (Zernichow et al, 2006;Korpetinou et al, 2014;Scuruchi et al, 2019).…”

Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome

“…NIFK that encodes for a protein that functions in mitosis and progression of cell cycle 26 was found to be upregulated and associated with poor prognosis in lung cancer 49 . SRGN encodes for a proteoglycan in hematopoietic cells 26 and its overexpression is associated with poor prognosis in hepatocellular 50 , colorectal cancer 51 , non-small cell lung cancer 52 , and nasopharyngeal carcinoma 53 . CAMP that is also known as LL37 and CAP18, encodes for cathelicidin antimicrobial peptide 26 .…”

The role of SRGN in the survival and immune infiltrates of skin cutaneous melanoma (SKCM) and SKCM-metastasis patients

“…Nowadays, it has been demonstrated that SRGN can be secreted by various cells including tumor cells [16]. In previous studies, most researches found that high SRGN expression was correlated with low survival rate of most tumors such as breast cancer [33], prostate cancer [34], colorectal cancer [15], nasopharyngeal carcinoma [17], glioma [35], and primary lung adenocarcinomas [36]. However, the role of SRGN in melanoma has not been explored before.…”

“…It contains a peptide core of 17.6 kDa which is rich in serine-glycine repeats and has eight glycosaminoglycan (GAG) side chains [11]. A series of evidences have demonstrated that SRGN involves in the progression of tumors including acute myeloid leukemia [12], breast cancer [13,14], colorectal cancer [15], nasopharyngeal carcinoma [16,17], multiple myeloma [18], and etc. [19].…”